Use of 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine and its physiologically acceptable salts

ABSTRACT

1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine or a physiologically acceptable salt thereof, for the treatment of sub-type anxiety disorders chosen from the sub-types: panic disorder with or without agoraphobia, agoraphobia, obsessive-compulsive spectrum disorders, social phobia, posttraumatic stress disorder, acute stress indication or generalized anxiety disorder, bipolar disorders, mania, dementia, substance-related disorders, sexual dysfunctions, eating disorders, obesity, anorexia, and fibromyalgia. A preferred salt is 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine hydrochloride.

This application is a divisional of U.S. application Ser. No.09/979,922, filed Apr. 8, 2002, now U.S. Pat. No. 6,900,212, whichclaimed priority of EP 99 109295.8, filed May 27, 1999, and which is a371 of PCT/EP00/04376, filed May 16, 2000.

The present invention relates to the use of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineor a physiologically acceptable salt thereof, for the manufacture of amedicament for the treatment of sub-type anxiety disorders.

1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine,physiologically acceptable salts thereof (U.S. Pat. No. 5,532,241,column 7, lines 30 to 58) and a process (U.S. Pat. No. 5,532,241,Example 4) by which it/they can be prepared are known from U.S. Pat. No.5,532,241. The compound which is referred to herein is described in thepatent as a combined selective serotonin (5-HT) reuptake inhibitor(SSRI) and 5-HT_(1A) receptor agonist. Therefore, the use of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineand its physiologically acceptable acid addition salts for themanufacture of a medicament for the treatment of depressive disorders,including the sub-type disorders major depressive disorder and dysthymicdisorder, for the treatment of anxiety disorders, for the treatment ofpsychiatric disorders like psychoses, schizophrenia or schizoaffectivedisorder, for the treatment of cerebral infarct like stroke and cerebralischemia, for the treatment of CNS disorders such as tension, for thetherapy of side-effects in the treatment of hypertension (e.g. withα-methyldopa) and for the prophylaxis and therapy of cerebral disorders(e.g. migraine) is disclosed. Additionally, the use in endocrinology andgynecology is described, e.g. for the treatment of acromegaly,hypogonadism, secondary amenorrhea, premenstrual syndrome or undesiredpuerperal lactation.

Furthermore, it is known that they have a useful potential utility forthe treatment of sleep disorders, including dyssomnias and narcolepsy.

The invention had the object of providing novel uses for1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineand its physiologically acceptable salts having significantly betterpharmacological properties than compounds of the prior art.

It has been found that1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinealso has activity against sub-type anxiety disorders chosen from thesub-types panic disorder with and/or without agoraphobia, agoraphobia,obsessive-compulsive spectrum disorders, social phobia, specific phobiaincluding neophobia, posttraumatic stress disorder, acute stressindication or generalized-anxiety disorder.

Accordingly, the present invention relates to the use of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineor a physiologically acceptable salt thereof, for the manufacture of amedicament for the treatment of sub-type anxiety disorders chosen fromthe sub-types panic disorder with or without agoraphobia, agoraphobia,obsessive-compulsive spectrum disorders including obsessive compulsivedisorders, social phobia, specific phobia including neophobia,posttraumatic stress disorder, acute stress indication and/orgeneralized-anxiety disorder.

It is known that 5-HT reuptake inhibitors such as fluoxetine (L. Solyom,C. Solyom, B. Ledwidge, Can. J. Psychiatry, 1991, 36: 378-380) or5-HT_(1A) receptor agonists such as geprione (J. C. Pecknold, L. Luthe,M. H. Scott-Fleury, S. Jenkins, J. Clin. Psychopharmacology, 1993, 13:145-149) are clinically effective in panic disorders. It has been foundthat a combined elective 5-HT reuptake inhibitor and 5-HT_(1A) receptoragonist which includes both mechanisms leads to an advantage in clinicalpractice.

A typical model for panic disorder is the Mouse Defense Test Batteryaccording to G. Griebel, D. C. Blanchard, R. J. Blanchard, Prog.Neuropsychopharmacol. & Biol. Psychiat, 1996, 20: 185-205. The mousedefence battery test consists of an oval runway of 2 m straight segmentsjoint by two 0.4 m curved segments separated by a median wall. A mouseis placed in the runway for a 3 min familiarization period. Then, ahand-held anaesthetized rat is introduced into the runway and brought upto the mouse. Approach is terminated when contact with the mouse wasmade or the mouse runs away from the approaching rat. If the subjectruns away, avoidance distance and the number of avoidances after fiveapproaches are recorded. Immediately after these approaches, the ratchases the mouse for a distance of 15 m, and flight speed is recorded.

A typical model for Agoraphobia is named Elevated Plus Maze according toS. Pellow, P. Chopin, S. E. File, M. Briley, J. Neurosci. Meth., 1985,14: 145-167.

The apparatus consists of an X-shaped platform elevated from the floor,with two “open” unprotected arms and two “closed” protected arms, withanimals having free access to both arms. The rat or mouse is placed inthe centre of the arms, and the number of entires made and the timespent on the open arms is measured in a 3 min test period. Normalanimals have very low basal levels, i.e. avoid entering the open armsand stay only a for a very brief period on open arms.

1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineor one of its physiologically acceptable salts, in particular1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride, following oral application dose-dependently increasedboth the number of entries and the time spend on open arms. For example,in mice the dose of 10 mg/kg p.o. increased the number of entires by157% and time spent on open arms by 105%. In rats, a dose of 10 mg/kgp.o. increased number of entries by 56% and time spent on open arms by76%.

It is known that 5-HT reuptake inhibitors such as paroxetine (A. K.Cardogan, I. K. Wright, I. Combs, C. A. Marsden, D. A. Kendall, I.Tulloch, Neurosci. Lett. 42: S8) or 5-HT_(1A) receptor agonists such asgeprione (V. Motta, S. Maisonnette; S. Morato; P. Castrechini; M. L.Brandao, Psychopharmacology, 1992; 107: 135-139) or 8-OH-DPAT(8-hydroxy-dipropylaminotetralin) (N. Collinson, G. R. Dawson,Psychopharmacology, 1997, 132: 35-43) have been shown to be effective inthe elevated plus maze test. It has been found that a combined selective5-HT reuptake inhibitor and 5-HT_(1A) receptor agonist which includesboth mechanisms leads to therapeutic advantages.

Obsessive Compulsive Disorders (OCDs) are characterized by unwantedintrusive, recurring thoughts, images, or actions which generate anirrational dread (obsession) of germs, dirt, contamination, apprehensionof acting on violent or aggressive impulses, feeling overly responsiblefor the safety of others, e.g. unreasonable dread of having run oversomeone with a car, abhorrent religious (blasphemous) and sexualthoughts, inordinate concern with order, arrangement, or symmetry,inability to discard useless or worn out possessions.

This often results in the repetitive performance of rituals(compulsions), such as excessive washing (particularly hand-washing orbathing), touching, counting, arranging and ordering, checking, cleaningand hoarding which persons suffering from OCD feel they can not control.Performing these rituals, however, provides only temporary relief. Thisperson is almost always aware that their strange compulsive behaviourmakes no sense, but feels helpless to stop it. This person can have afew or many of these symptoms, which can vary during the course of thedisorder. The patterns may be repeated as much as 100 times or forseveral hours per day, and renders the person unable to functionnormally (for review e.g. Dolberg et al., Clin. Neuropharmacol. 1996,19: 129 or F. Tallis, Br. J. Clin. Psychol. 1997, 36: 3).

Obsessive Compulsive Spectrum Disorders (OCSDs) share common featureswith OCDs including overlapping symptom profiles, demographics, familyhistory, comorbidity, clinical course and response to anti-obsessionaltreatment.

OCSDs include e.g. somatoform disorders (e.g. body dysmorphobia,hypochondriasis), tic disorders (e.g. Gilles de la Tourette's syndrome),impulsive personality disorders (e.g. antisocial personality disorder),impulse control disorders (e.g. trichotillomania, kleptomania,pyromania, pathological gambling, sexual compulsions such asexhibitionism, voyeurism, fetishism), schizo-obsessive disorders(e.g.obsessional schizophrenia, schizotypic OCD, delusional OCD),dissociative disorders (e.g. autism, torticolis, Sydenham's Chorea,Asperger's syndrome) [for review e.g. E. Hollander and C. Wong, J. Clin.Psychiatry 1995, 56 (suppl. 4): 3 or McElroy et al., J. Clin. Psychiatry1994, 55 (suppl. 10): 33].

A typical model for OCSD including OCD is the Marble Burying Testaccording to Y. Ichimaru, T. Egawa, A. Sawa, Jpn. J. Pharmacol. 1995,68: 65-70.

The apparatus consists of an open cubic box with 25 clean glass marblesevenly spaced on sawdust. Individual mice are placed in the test box,and the number of glass marbles left uncovered after 20 minutes arecounted.1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineor one of its physiologically acceptable salts, in particular1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride, following subcutaneous application inhibits mable buryingin mice dose-dependently. For example, a dose of 3 mg/kg of1-[4(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride nearly completely (92%) inhibits marble burying;equieffective doses of conventional serotonin reuptake inhibitors aree.g. 20 mg/kg for fluvoxamine or 17 mg/kg for fluoxetine and anequieffective dose of the 5-HT_(1A) agonist ipsapirone is 10 mg/kg.

It is known that 5-HT reuptake inhibitors or 5-HT_(1A) receptor agonistsinhibit marble burying, e.g. fluvoxamine, citalopram or 8-OH-DAPT,gepirone (K. Njung'e, S. L. Handley, Br. J. Pharmacol., 104: 105-112;).So-far the selective serotonine reuptake inhibitors (SSRIs) are chosenfor the treatment of OCSD (W. K. Goodman, L. H. Price, P. L. Delgado,Arch. Gen. Psychiatry 1990, 47: 577-585). It has been found that acombined selective 5-HT reuptake inhibitor and 5-HT_(1A) receptoragonist has an increased activity and a faster onset of action.

A model for social phobia is the Social Interaction Test according to S.File, J. R. G Hyde, J. Pharm. Pharmacol. 1977, 29: 735-738.

Pairs of rats not familiar with each other are placed in an open testbox brightly lit (aversive condition), and the number and duration ofsocial contacts during a 5 min test session are recorded.

1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineor one of its physiologically acceptable salts, in particular1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride, increase the time spent in social interaction. Forexample, for an oral dose of 10 mg/kg of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride the pairs of rats unfamiliar to each other spend 144 secof the 300 sec of total time with social interaction compared to 116 secfor the vehicle treated pairs of rats.

It is known that the 5-HT reuptake inhibitor paroxetine (S. Lightowler,I. J. R. Williamson, J. Hegarty, G. A. Kennett, R. B. Fears, I. F.Tulloch, Br. J. Pharmacol. 1992, 106: 44P) or the 5-HT_(1A) receptoragonists 8-OH-DPAT or ipsapirone (G. A. Higgins; A. J. Bradbury; B. J.Jones; N. R. Oakley, Neuropharmacology, 1988, 27: 993-1001) increasesocial interaction behaviour. It has been found that a combinedselective 5-HT reuptake inhibitor and 5-HT_(1A) receptor which includesboth mechanisms leads to therapeutic advantages.

A model for specific phobia is the Shock-Probe Test according to D.Treit, M. A. Fundytus, Pharmacol. Biochem. Behav. 1988, 30: 1071-1075.Individual rats are habituated for 30 min each of 4 days to an open boxfilled with sawdust. On the test day, a continuously electrified probeis inserted 2 cm above the ground. The number of contacts with the probeis counted and the attemps to cover the probe with sawdust are recorded.

It is known that the serotonin reuptake inhibitor imipramine (T. F.Meert, F. C. Colpaert, Psychopharmacology, 1986, 88: 445-450) or5-HT_(1A) receptor agonists, e.g. 8-OH-DPAT (D. Treit; A. Robinson; S.Rotzinger; C. Pesold, Behav-Brain-Res., 1993, 54: 23-34) or ipsapirone(S. M. Korte, B. Bohus, Eur. J. Pharmacol., 1990, 181: 307-10)demonstrated efficacy in this model. It has been found that a combinedselective 5-HT reuptake inhibitor and 5-HT_(1A) receptor which includesboth mechanisms leads to therapeutic advantages.

In a typical model for neophobia, mice deprived from food for 18 h aregiven access to unfamiliar food in a novel environment [P. Soubrie etal., Psychopharmacologica, 1975, 45: 203-210].1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineor one of its physiologically acceptable salts, in particular1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride, following oral application increased food intake by 21%at the dose of 3 mg/kg.

Animal models of anxiety associated with posttraumatic stress in ratsutilize the long-lasting behavioural changes induced by exposure to anative stressor. The therapeutic effects of a compound effective for theacute treatment of anxiety associated with posttraumatic stress aremodelled by administration of the compound after exposure to thestressor. The therapeutic effects of a compound effective for theprophylactic treatment of anxiety associated with posttraumatic stressare modelled by administration of the compound before exposure to thestressor. Amongst the several behavioral test procedures, the followingis most validated [R. E. Adamec and T. Shallow, Physiology Behavior,1993, 54: 101-109; R. E. Adamec et al., Behav. Neurosci. 1997, 111:435-449]. In general, a rat is exposed to a cat for five minutes, andseven days later the rat can be tested in a battery of tests, i.e. thehole board test, the elevated plus maze and the acoustic startle test.The hole board consists of a box (60 cm×60 cm) with four evenly spacedholes; the number of poking its head into a hole is counted for 5minutes. The elevated plus maze consists of an X-shaped platformelevated from the floor, with two “open” unprotected arms and two“closed” protected arms, with rats having free access to both arms. Therat is placed in the centre of the arms, and the frequency of attemptsto enter an open arm (risk assessment) as well as the time spent on theopen and closed arms are measured. In the acoustic startle test, the ratis placed in a plexiglass cylinder, and a series of 20 white noisebursts of 120 dB out of a background noise of 60 dB is applied, and thelatency to and the peak startle amplitude are measured. In general, ratsexposed to the a stressor like a cat show a reduced number of head dipsinto the holes, have a lower risk assessment and spend less time on theopen arms, and the startle response is increased.

1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineor one of its physiologically acceptable salts, in particular1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride, are effective in the models for anxiety associated withposttraumatic stress when given after (acute treatment) and before(prophylactic treatment) the cat stressor.

A typical clinical study for post traumatic stress disorder is describedin the following.

Twenty (20) male or female patients aged 18-65 years suffering fromnon-combat related chronic post traumatic stress disorder as defined byDSM-IV (Diagnostic and Statistical Manual for Mental Disorders, FourthVersion) will be treated for a 12 week period. Ten patients will beassigned randomly to receive1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineor a physiologically acceptable salt thereof and 10 patients willreceive matched placebo in a double-blind fashion.

Outcome will be assessed by the treating physician and the patient withthe use of the Hamilton Depression Rating Scale, the Montgomery-AsbergDepression Rating Scale, The Clinical and Patient Global ImpressionScales, general symptoms and specific rating of PTSD core symptoms usingthe Clinician Administered PTSD Scale according to D. Blake et al,Behavioral Therapy 1990, 13: 187-188 and TOP-8 scale according to J. R.T. Davidson et al, International Clinical Psychopharmacology 1997, 12:41-45.

A typical model for acute stress indication is the Four Plate Testaccording to C. Aron, P. Simon, C. Larousse, J. R. Boissier,Neuropharmacology 1971, 10: 459-469.

The apparatus consists of small box with a floor made up of four metalplates. Each time the mouse crosses from one plate to another, it isgiven a brief electric footshock reducing the amount of exploratorybehavior. The number of punished crossings from one plate to another(i.e. number of shocks accepted by the animal) is recorded during a fiveminute test period. Normal mice make only few punished crossings, i.e.accept only a few footshocks.

1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride following and oral dose of 3 mg/kg increased the number ofpunished crossings by 41%.

This model has been validated with clinically active benzodiazepines inthe literature (e.g. D. N. Stephens, W. Kehr, Psychopharmacology 1985,85: 143-147; G. D. Bartoszyk, U. Schoenherr, Behav. Neural Biol. 1987,48: 317-9). It has been found that a combined selective 5-HT reuptakeinhibitor and 5-HT_(1A) receptor leads to therapeutic advantages becauseit avoids the sedative properties of benzodiazepines.

A typical model for generalized anxiety disorders is the Light-DarkChoise Test (Passive Avoidance Test) according to J. N. Crawly,Pharmacol. Biochem Behav. 1981, 15: 695-699.

The light-dark choise apparatus consists of two connected boxes with onebox darkened and the other one highly illuminated. A mouse is placed inone box, and the time spent in lit box and the number of transitionsbetween boxes are measured over a period of 5 min. Normal mice only havelow numbers of entries to the lit compartment and spent most time in thedark compartment.

1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineor one of its physiologically acceptable salts, in particular1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride, following oral application dose-dependently increase thenumber of transitions and time spent in lit compartment. For example, anoral dose of 10 mg/kg of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride increased the number of transitions by 73% and time spentin lit compartment by 31%.

It is known from the 5-HT reuptake inhibitors, imipramine (R. Young, D.N. Johnson, Pharmacol. Biochem. Behav., 1991, 40: 739-743), or the5-HT_(1A) receptor agonists e.g. 8-OH-DPAT and ipsapirone (B. Costall;A. M. Domeney, A. J. Farre; M. E. Kelly; L. Martinez; R. J. Naylor, J.Pharmacol. Exp. Ther., 1992, 262: 90-98) that they increase time spentin illuminated compartment and number of transitions betweencompartments. It has been found that a combined selective 5-HT reuptakeinhibitor and 5-HT_(1A) receptor which includes both mechanisms leads totherapeutic advantages.

A preferred salt of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineis1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride.

Therefore the invention relates to the use for the manufacture of amedicament for the treatment of sub-type anxiety disorders in which thepharmacologically acceptable salt is1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride.

Additionally, the invention relates to the use of a pharmaceuticalcomposition containing at least one compound of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineand/or one of its biocompatible salts together with at least one solid,liquid or semiliquid excipient or adjunct for the treatment of sub-typeanxiety disorders chosen from the sub-types panic disorder with and/orwithout agoraphobia, agoraphobia, obsessive-compulsive spectrumdisorders, social phobia, specific phobia including neophobia,posttraumatic stress disorder, acute stress indication orgeneralized-anxiety disorder.

Thus the invention provides a pharmaceutical preparation for thetreatment of such sub-type anxiety disorders characterized in that itcontains at least1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineor one of its pharmaceutically acceptable salts.

The compounds,1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineand its pharmaceutically acceptable salts, according to the inventionare preferably administered in analogy to other known commerciallyavailable preparations for the treatment of sub-type anxiety disorders(e.g. fluoxetine, fluvoxamine). A unit dose will generally contain from0.1 to 1000 mg, preferably between approximately 0.1 and 500 mg, inparticular 5, 10, 20, 30, 40, 50, 100, 150, 200, 250 and 300 mg. Thecomposition may be administered once or more times a day for example 2,3 or 4 times daily. The daily dose is preferably between approximately0.01 and 50 mg/kg of body weight. However, the specific dose for eachpatient depends on all sorts of factors, for example on the activity ofthe specific compound employed, on the age, body weight, general stateof health, sex, on the diet, on the time and route of administration, onthe excretion rate, pharmaceutical substance combination and severity ofthe particular disorder to which the therapy relates. Oraladministration is preferred, but also peroral routes of administration(e.g. intraveneous or transdermal) can be utilized.

Additionally, it has been surprisingly found that1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinealso has activity against bipolar disorders and/or mania.

A typical animal model of mania/bipolar disorders is the hyperactivityinduced by a mixture of dexamphetamine and chlordiazepoxide according toA. L. Vale and F. Ratcliffe, Psychopharmacology, 1987; 91: 352-355. andB. J. Cao and N. A. Peng, Eur. J. Pharmacol., 1993; 237: 177-181. Thedexamphetamine-chlordiazepoxide mixture induces strong hyperactivity inmice or rats.

1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineor one of its physiologically acceptable salts, in particular1-[-4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride, inhibit the hyperactivity induced by the mixture to thesame degree as do lithium and valproate, the standard treatments formania and bipolar disorders.

Accordingly, the present invention relates to the use of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineor a physiologically acceptable salt thereof, for the manufacture of amedicament for the treatment of bipolar disorders and/or mania.

A typical clinical study for bipolar disorders and/or mania is describedin the following.

Twenty (20) male or female patients aged 18-65 years suffering from anacute hypomanic episode as part of a Bipolar II Disorder as diagnosed byDSM-IV will be treated for a 3 week period with either1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineor one of its physiologically acceptable salts or lithium in adouble-blind fashion.

Clinical improvement will be assessed by means of the Mania sub-scale ofthe SADS-C according to R. R. Lewine et al., Schizophr. Bull. 1983,9(3): 368-76, the Young Mania Rating Scale according to R. G. Cooke etal, Biol-Psychiatry. 1996, 40(4): 279-83, the Hamilton Depression RatingScale according to M. Hamilton, Journal of Neurology, Neurosurgery andPsychiatry 1960, 23: 56-62, the Global Assessment Scale according to J.Endicott et al., Arch. Gen. Psychiatry, 1976, 33(6): 766-71 and theClinical Global Improvement Scale according to W. Guy (ed.), ECDEUAssessment for Psychopharmacology, 1976, 217-222 at weekly intervals.The results of this study will be used to determine if1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineor one of its physiologically acceptable salts exhibit acute anti-manicproperties, prior to a long-term prophylaxis study.

The invention relates furthermore to the use for the manufacture of amedicament for the treatment of bipolar disorders and/or mania in whichthe pharmacologically acceptable salt is1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride.

Thus the invention relates to the use of a pharmaceutical compositioncontaining at least one compound of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineand/or one of its biocompatible salts together with at least one solid,liquid or semiliquid excipient or adjunct for the treatment of bipolardisorders and/or mania.

Thus the invention provides a pharmaceutical preparation for thetreatment of bipolar disorders and/or mania characterized in that itcontains at least1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineor one of its pharmaceutically acceptable salts.

The compounds according to the invention are preferably administered inanalogy to other known commercially available preparations for thetreatment of bipolar disorders and/or mania (e.g. fluoxetine,fluvoxamine), preferably in doses of between approximately 0.1 and 500mg, in particular between 5 and 300 mg per dose unit. The daily dose ispreferably between approximately 0.01 and 10 mg/kg of body weight.However, the specific dose for each patient depends on all sorts offactors, for example on the activity of the specific compound employed,on the age, body weight, general state of health, sex, on the diet, onthe time and route of administration, on the excretion rate,pharmaceutical substance combination and severity of the particulardisorder to which the therapy relates. Oral administration is preferred,but also peroral routes of administration (e.g. intraveneous ortransdermal) can be utilized.

Additionally, it has been surprisingly found that1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinealso has activity against dementia, including Alzheimer's disease andmulti-infarct.

Accordingly, the present invention relates to the use of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineor a physiologically acceptable salt thereof, for the manufacture of amedicament for the treatment of dementia.

Typical models for dementia, Alzheimer's disease and multi-infarct arethe Passive Avoidance test in rats [S. D. Glick and B. Zimmerberg,Behav. Biol., 1972, 7: 245-254; D. K. Rush, Behav. Neural Biol., 1988,50: 255-274] and the testing of memory functions in the Morris WaterMaze in aged rats [R. Morris, J. Neurosci. Methods, 1984, 11: 47-60; F.H. Gage et al.; Neurobiol. Aging. 1984, 5: 43-48].

For the Passive Avoidance test, the apparatus is a runway separated froma dark compartment by a small door. The amnestic drug scopolamine isadministerd before the animal is submitted to an aquisition trial: therat is placed on the entry of the runway opposite to the darkcompartment, the latency to enter the dark compartment is recorded, andonce the rat has entered the dark compartment, the door is closed and afoot schock is administered via the gridfloor. A retention trial isperformed 48 h later identical to the aquisition trial (withoutscopolamine) and the latency to enter the dark compartment recordedagain. Normal scopolamine-treated animals do not remember the foot shockfrom the aquisition trial and enter the compartment with similarlatencies in the retention trial.

1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineor one of its physiologically acceptable salts, in particular1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride, following oral application of 10 mg/kg p.o. enhancedmemory, i.e. the latency to enter the dark compartment in the firstretention trial was increased by 78% compared to untreated rats.

It is known that serotonin reuptake inhibitors such as fluoxetinecounteract scopolamine-induced cognitive deficits-(S. Kumar, S. K.Kulkami, Indian J. Exp. Biol., 1996, 34: 431-435), and the involvementof 5-HT_(1A) receptors in the dorsal raphe has been demonstrated (M.Carli, P. Bonalumi, R. Samanin, Eur. J. Neurosci. 1998, 10: 221-30). Ithas been found that a combined selective 5-HT reuptake inhibitor and5-HT_(1A) receptor devoid of cholinergic properties leads to a majortherapeutic advancement.

The Morris Water Maze consists of a circular water tank (150 cm indiameter) filled with water with an escape platform (15 cm in diameter)18 cm from the periphery beneath the surface of the water. The water ismade opaque rendering the platform invisible. Rats placed in the tankswim around and find the hidden platform accidently after a certain time(latency), and the latency to find the platform is taken as measure.When given further training session to find the platform, rats showreduced latencies from day to day, i.e. remember (learn) the location ofthe platform. But compared to young rats, aged rats perform less well inlearning over days reflecting impaired learning capacity. Drugseffective for dementia and particularly Alsheimers disease improve thelearning capacity of aged rats.

1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride is adminstered to old rats at oral doses of 1 and 3 mg/kgevery day. When tested at day 7, the latencies to find the platform inthe first attempt are 77 sec (1 mg/kg) and 73 sec (3 mg/kg) notdiffering from vehicle treated young rats (76 sec) whereas untreated oldrats needed 95 sec to find the platform.

The invention relates furthermore to the use for the manufacture of amedicament for the treatment of dementia in which the pharmacologicallyacceptable salt is1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride.

Furthermore, the invention relates to the use of a pharmaceuticalcomposition containing at least one compound of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineand/or one of its biocompatible salts together with at least one solid,liquid or semiliquid excipient or adjunct for the treatment of dementia.

Thus the invention provides a pharmaceutical preparation for thetreatment of dementia characterized in that it contains at least1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineor one of its pharmaceutically acceptable salts.

The compounds according to the invention are preferably administered inanalogy to other known commercially available preparations for thetreatment of dementia including Alzheimer's disease and multi-infarct(e.g. fluoxetine, fluvoxamine), preferably in doses of betweenapproximately 0.1 and 500 mg, in particular between 5 and 300 mg perdose unit. The daily dose is preferably between approximately 0.01 and50 mg/kg of body weight. However, the specific dose for each patientdepends on all sorts of factors, for example on the activity of thespecific compound employed, on the age, body weight, general state ofhealth, sex, on the diet, on the time and route of administration, onthe excretion rate, pharmaceutical substance combination and severity ofthe particular disorder to which the therapy relates. Oraladministration is preferred, but also peroral routes of administration(e.g. intraveneous or transdermal) can be utilized.

Additionally, it has been surprisingly found that1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinealso has activity against substance-related disorders.

Accordingly, the present invention relates to the use of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineor a physiologically acceptable salt thereof, for the manufacture of amedicament for the treatment of substance-related disorders.

Substance-related disorders include substance dependence with or withoutits withdrawal symptoms, substance-induced mood disorder andsubstance-induced anxiety disorder. “Substance” is herein defined asalcohol, amphetamine, cannabis, cocaine, hallucinogen, opoid,phencyclidine, nicotine and/or tobacco for substance dependence.“Substance” is defined as alcohol, amphetamine, cocaine, hallucinogen,inhalant, opoid and/or phencyclidine for substance-induced mood disorderand for substance-induced anxiety disorder.

It has been found that1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineis preferably active against alcohol-dependance and/or against nicotine(tobacco) withdrawal symptoms. Nicotine withdrawal symptoms includerestlessness, irritability, drowsiness, increasingly frequent wakingsfrom sleep, impatience, confusion, impaired concentration, carbohydratecraving and weight gain, impaired reaction time and a craving fortobacco.

In particular,1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineis active against alcohol-dependence.

It is known that increased synaptic 5-HT content effectively reducesalcohol consumption in alcohol-preferring rats (F. C. Zhou, D. L.McKinzie, T. D. Patel, Li Lumeng, T. K. Li, Alcohol Clin Exp. Res. 1998,22 (1): 266-269.) Accordingly, alcohol-preferring rats were treated withthe test compound twice daily subcutaneously. Ethanol drinking, waterintake and bodyweight were determined over 24 h. Baseline ethanol intakewas derived from the mean ethanol intakes of the three previous non-drugdays.

The invention relates furthermore to the use for the manufacture of amedicament for the treatment of substance-related disorders in which thepharmacologically acceptable salt is1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride.

A typical animal model is the drug discrimination procedure in ratsusing cocaine as the stimulus cue (e.g. D. M. Wood and M. W.Emmett-Oglesby, J. Pharmacol. Exp. Ther., 1986; 237: 120-125; D. Huangand M. C. Wilson, Pharmacol. Biochem. Behav., 1986; 24: 205-210; J. M.Witkin at al., J. Pharmacol. Exp. Ther., 1991; 257: 706-713). Rats aretrained to discriminate 10 mg/kg cocaine from saline in a two-leverdiscrimination procedure. Compounds which substitute for cocaine producea dose-dependent increase in cocaine-appropriate responding, i.e. inselecting the cocaine-paired lever.

1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineor one of its physiologically acceptable salts, in particular1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride, dose-dependently but only partially substituted forcocaine (maximally 60% choise of cocaine-paired lever at 50 mg/kg p.o.).Because1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride in contrast to cocaine does not serve as a stimulus drugby itself indicating lack of abuse potential, the generalzation tococaine indicates therapeutic benefit.

Additionally, the invention relates to the use of a pharmaceuticalcomposition containing at least one compound of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineand/or one of its biocompatible salts together with at least one solid,liquid or semiliquid excipient or adjunct for the treatment ofsubstance-related disorders.

Thus the invention provides a pharmaceutical preparation for thetreatment of substance-related disorders characterized in that itcontains at least1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineor one of its pharmaceutically acceptable salts.

The compounds according to the invention are preferably administered inanalogy to other known commercially available preparations for thetreatment of substance-related disorders (e.g. fluoxetine, fluvoxamine),preferably in doses of between approximately 0.1 and 1000 mg, inparticular between 5 and 500 mg per dose unit. The composition may beadministered once or more times a day for example 2, 3 or 4 times dailyor in sustained release form. The daily dose is preferably betweenapproximately 0.01 and 100 mg/kg of body weight. However, the specificdose for each patient depends on all sorts of factors, for example onthe activity of the specific compound employed, on the age, body weight,general state of health, sex, on the diet, on the time and route ofadministration, on the excretion rate, pharmaceutical substancecombination and severity of the particular disorder to which the therapyrelates. Oral administration is preferred, but also peroral routes ofadministration (e.g. intraveneous or transdermal) can be utilized.

Additionally, it has been surprisingly found that1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinealso has activity against sexual dysfunctions including prematureejaculation.

Accordingly, the present invention relates to the use of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineor a physiologically acceptable salt thereof, for the manufacture of amedicament for the treatment of sexual dysfunctions.

The term “premature ejaculation” includes congenital prematureejaculation as well as primary premature ejaculation.

In animal models, various behavioural measures for sexual function canbe used in animal models depending on the targeted dysfunction inhumans, e.g. reduced libido, anorgasmia, or ejaculation disorders.Measures for sexual activity in animals include fascilitation orprolongation of penile errection, ejaculatory behaviour or frequency ofmating behaviour in male rats, or the percentage of receptive behavioursin female rats [e.g.: S. Ahlenius and K. Larsson, Neurochem. Res., 1997,22:1065-1070; S. Ahlenius and K. Larsson, Psychopharmacology, 1998, 137:374-382; J. Vega-Matuszcyk et al., Pharmacol. Biochem. Behav., 1998, 60:527-532; J. M. Cantor et al., Psychopharmacology, 1999; 144: 355-362].

1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineor one of its physiologically acceptable salts, in particular1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride, were effective on various measures mentioned before.

A typical clinical study for sexual dysfunctions including prematureejaculation is described in the following.

Twenty (20) male patients aged 18-45 years suffering from majordepressive disorder together with a history of sexual dysfunction undertreatment with Selective Serotonin Reuptake Inhibitor antidepressantswill be treated for a 4 week period with1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5yl)-piperazineor a physiologically acceptable salt thereof. Assessment of sexualfunction and satisfaction will be evaluated using a series of questionsto each patient at weekly intervals. (Ref.: A. Feiger et al., J. Clin.Psychiatry 1996, 57(suppl 2): 53-62.

The invention relates furthermore to the use for the manufacture of amedicament for the treatment of sexual dysfunctions in which thepharmacologically acceptable salt is1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride.

Additionally, the invention relates to the use of a pharmaceuticalcomposition containing at least one compound of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineand/or one of its biocompatible salts together with at least one solid,liquid or semiliquid excipient or adjunct for the treatment of sexualdysfunctions.

Thus the invention provides a pharmaceutical preparation for thetreatment of sexual dysfunctions characterized in that it contains atleast1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineor one of its pharmaceutically acceptable salts.

The compounds according to the invention are preferably administered inanalogy to other known commercially available preparations for thetreatment of sexual dysfunctions including premature ejaculation (e.g.fluoxetine, fluvoxamine), preferably in doses of between approximately0.1 and 500 mg, in particular between 5 and 300 mg per dose unit. Thedaily dose is preferably between approximately 5 and 100 mg/kg of bodyweight for a time period of at least about 3 months, preferably for atime period of at least about 6 months. However, the specific dose foreach patient depends on all sorts of factors, for example on theactivity of the specific compound employed, on the age, body weight,general state of health, sex, on the diet, on the time and route ofadministration, on the excretion rate, pharmaceutical substancecombination and severity of the particular disorder to which the therapyrelates. In some instances the compounds of the present invention areadministered chronically as long as the patient remains sexually active.Oral administration is preferred, but also peroral routes ofadministration (e.g. intraveneous or transdermal) can be utilized.

Additionally, it has been surprisingly found that1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinealso has activity against eating disorders including anorexia nervosaand bulimia nervosa and/or obesity.

Accordingly, the present invention relates to the use of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineor a physiologically acceptable salt thereof, for the manufacture of amedicament for the treatment of eating disorders and/or obesity and/oranorexia.

A typical animal model for eating disorders and/or obesity and/oranorexia is named Cumulative Food Intake according to H. C. Jackson, A.M. Needham, L. J. Hutchins, S. E. Mazurkiewicz, D. J. Heal, Br. J.Pharmacol., 1997, 121: 1758-1762, which can be utilized in variousspecies. Usually, rats or mice are given free access to food, and thedevelopment of body weight is measured over time. The test can beperformed in both starved and non-starved rats or mice. Moreover,chronic or acute administration of a medication can be investigated.

1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride given orally up to 360 mg/kg for 4 consecutive days torats or mice with free access to food result in a reduced development ofbody weight at higher doses. On the other hand, the lower doses of up to50 mg/kg result in increased body weight. A reduced development of bodyweight was also observed in dogs. Thus, differential effects on bodyweight indicating therapeutic efficacy in either obesity or anorexiadepending on the dose range used are evident.

It is known that serotonin reuptake inhibitors such as fluoxetine,fluvoxamine, paroxetine or sibutramine (e.g. K. Inoue, N. Kiriike, Y.Fujisaki, M. Kurioka, S. Yamagami, Physiol. Behav. 1997, 61: 603-608; R.Ciccocioppo, I Panocka, C. Polidori, C. T. Dourish, M. MassiPsychopharmacology 1997, 134: 55-63; H. C. Jackson, A. M. Needham, L. J.Hutchins, S. E. Mazurkiewicz, D. J. Heal, Br. J. Pharmacol., 1997, 121:1758-1762; S. Garattini, Obes. Res. 1995, 3 (Suppl 4): 463S-470S) reducefood intake dramatically. Particularly the presynaptic 5-HT_(1A)properties of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineor one of its physiologically acceptable salts are of interest becausethese receptors are involved in the inhibition of food intake andpotentiate the effects of serotonin reuptake inhibitors in a synergisticway (A. C. Trillat, I. Malagie, M. Mathe-Allainmat, M. C. Anmella, C.Jacquot, M. Langlois, A. M. Gardier, Eur. J. Pharmacol. 1998, 357:179-84; D. L. Li, R. M. A. Simmons, S. Iyengar, Brain Res. 1998, 781:119-26). It has been found that a combined selective 5-HT reuptakeinhibitor and 5-HT_(1A) receptor like1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineor one of its physiologically acceptable salts which includes bothmechanisms leads to therapeutic advantages.

A typical clinical study for anorexia nervosa is described in thefollowing. Twenty (20) female patients aged 18-40 years suffering fromanorexia nervosa as diagnosed by DSM-IV will be treated for an 12 weekperiod with either1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineor one of its physiologically acceptable salts or placebo in adouble-blind fashion.

Clinical improvement will be assessed by measurements of weight,menstruation status. Depressive symptoms will be assessed by use of theMontgomery Asberg Depression Rating Scale according to S. A. Montgomeryet al., British Journal of Psychiatry, 1979, 134: 382-389.

A typical clinical study for bulimia nervosa is described in thefollowing. Twenty (20) female patients aged 18-40 years suffering frombulimia nervosa as diagnosed by DSM-IV will be treated for a 8 weekperiod with either1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineor one of its physiologically acceptable salts or placebo in adouble-blind fashion.

Clinical improvement will be assessed by comparison of the frequency ofbinge-eating and vomiting episodes, and measurements of weight.

Associated symptoms of bulimia nervosa such as depression will beassessed by means of the Montgomery Asberg Depression Rating Scaleaccording to S. A. Montgomery et al., British Journal of Psychiatry,1979, 134: 382-389.

The invention relates furthermore to the use for the manufacture of amedicament for the treatment of eating disorders and/or obesity and/oranrexia in which the pharmacologically acceptable salt is1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride.

Additionally, the invention relates to the use of a pharmaceuticalcomposition containing at least one compound of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineand/or one of its biocompatible salts together with at least one solid,liquid or semiliquid excipient or adjunct for the treatment of eatingdisorders and/or obesity and/or anorexia.

Thus the invention provides a pharmaceutical preparation for thetreatment of eating disorders and/or obesity and/or anorexiacharacterized in that it contains at least1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineor one of its pharmaceutically acceptable salts.

The compounds according to the invention are preferably administered inanalogy to other known commercially available preparations for thetreatment of eating disorders and/or obesity and/or anrexia (e.g.fluoxetine, fluvoxamine), preferably in doses of between approximately0.1 and 500 mg, in particular between 5 and 300 mg per dose unit. Thedaily dose is preferably between approximately 0.01 and 10 mg/kg of bodyweight However, the specific dose for each patient depends on all sortsof factors, for example on the activity of the specific compoundemployed, on the age, body weight, general state of health, sex, on thediet, on the time and route of administration, on the excretion rate,pharmaceutical substance combination and severity of the particulardisorder to which the therapy relates. Oral administration is preferred,but also peroral routes of administration (e.g. intraveneous ortransdermal) can be utilized.

Additionally, it has been surprisingly found that1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinealso has activity against fibromyalgia.

Accordingly, the present invention relates to the use of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineor a physiologically acceptable salt thereof, for the manufacture of amedicament for the treatment of fibromyalgia.

Fibromyalgia, a chronic muscle disorder, is characterized by pain of thewhole locomotion system which is not caused by any inflammation orpsychological state of the patient combined with chronic fatiguesyndrome and multiple tender-points. Further symptoms are disturbance ofsleep, morning rigidity, headache, irritable bowel and bladder syndrome,and paresthesias. Patients suffering from fibromyalgia show no increasedvalues of inflammation or increased rheumatoid factors. According to aninquiry in the USA, 2% of the population are affected by fibromyalgia.

In the last years, some characteristics for diagnosis were developped(e.g. M. B. Yunus, Z. Rheumatol 1989, 48: 217-222) to differentiate fromoverlapping somatic or psychiatric disorders.

The reason for fibromyalgia is unknown but it is shown that theantidepressive drug amitryptiline gave positive results in clinicalstudies [L. Stander, CNS Drugs 1999, 11: 49-60].1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineand/or a physiologically acceptable salt thereof show similar influenceto the sleep regulatory system but posess no anticholinergicside-effects which are typical for tricyclic antideppressants.Furthermore, it is described that studies of the cerebrospinal fluidsupport a relationship between serotonin and fibromyalgia in certainareas of the central nervous system [I. J. Russell et al., ArthritisRheum 1992, 35: 550-556 and E. Houvenagel et al., Rev. Rheum. MalOsteoartic 1990, 57: 21-23].

Rapid procedures to test pain-relieving properties of drugs are theabdominal constriction (writhing) test according to E. Siegmund et al.,Proc. Soc. Exp. Biol. Med. 1957, 95: 729-731 and the intradermalformalin test accorrding to S. Hunskaar et al., J. Neurosci. Meth. 1985,14: 69-76. For example,1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride at 30 mg/kg p.o. reduced abdominal contrictions by 82%,and 10 mg/kg p.o. reduced the formalin-induced pain response by 79%.

A more sophisticated animal model for fibromyalgia is chronicconstrictions of the sciatic nerve in rats associated with hyperalgesia,allodynia and spontaneous pain [G. J. Bennett G. J. and Y. K. Xie, Pain1988, 33: 87-107]. In this model, rats are anesthesized and 4 ligaturesspaced 1 mm apart are loosely tied around the left sciatic nerve. Ratsare tested when the chronic state is fully installed, i.e. one weekafter sciatic nerve surgery, for reactivity to thermal and tactilestimulation. A rat is placed in a box. For thermal stimulation, aninfrared radiant source is focused under the non-lesioned and lesionedhindpaws and the hindpaw withdrawal latencies are recorded. For tactilestimulation, the tip of an electronic Von Frey probe is applied withincreasing pressure on the non-lesioned and lesioned hindpaws, and theforce required to induce a paw-withdrawal is recorded.

A typical clinical study for fibromyalgia is described in the following.Twenty (20) male or female patients aged 18-65 years suffering fromfibromyalgia will be treated with1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineor a physiologically acceptable salt thereof for eight weeks in an openlabel clinical study. Assessment of clinical improvement will be made bymeans ratings of pain symptoms on a 100 mm Visual Analogue Scale foroverall pain, and by the McGill pain questionaire according to R.Meizack, Pain 1987, 30:191-197. Depressive symptoms will be assessed bymeans of the Montgomery Asberg Depression Rating Scale according to S.A. Montgomery et al., British Journal of Psychiatry, 1979, 134: 382-389and the Hamilton Depression Rating Scale according to M. Hamilton,Journal of Neurology, Neurosurgery and Psychiatry, 1960, 23: 56-62.

Clinical improvement could be also assessed by means of the number ofpositive tender points (TP score≧11 from 18) according to the ACRcriteria (Arthritis Rheum. 1990, 33: 160-172) for the diagnosis offibromyalgia.

The invention relates furthermore to the use for the manufacture of amedicament for the treatment of fibromyalgia in which thepharmacologically acceptable salt is1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride.

Additionally, the invention relates to the use of a pharmaceuticalcomposition containing at least one compound of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineand/or one of its biocompatible salts together with at least one solid,liquid or semiliquid excipient or adjunct for the treatment offibromyalgia.

Thus the invention provides a pharmaceutical preparation for thetreatment of fibromyalgia characterized in that it contains at least1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineor one of its pharmaceutically acceptable salts.

The compounds according to the invention are preferably administered inanalogy to other known commercially available preparations for thetreatment of fibromyalgia (e.g. amitryptiline), preferably in doses ofbetween approximately 0.1 and 500 mg, in particular between 5 and 300 mgper dose unit. The daily dose is preferably between approximately 0.01and 10 mg/kg of body weight. However, the specific dose for each patientdepends on all sorts of factors, for example on the activity of thespecific compound employed, on the age, body weight, general state ofhealth, sex, on the diet, on the time and route of administration, onthe excretion rate, pharmaceutical substance combination and severity ofthe particular disorder to which the therapy relates. Oraladministration is preferred, but also peroral routes of administration(e.g. intraveneous or transdermal) can be utilized.

All the pharmaceutical preparations used for the treatment of sub-typeanxiety disorders, bipolar disorders, mania, dementia, substance-relateddisorders, sexual dysfunctions, eating disorders, obesity, anorexia orfibromyalgia can be used as pharmaceuticals in human or veterinarymedicine.

A process for the manufacture of a pharmaceutical preparation used forthe treatment of sub-type anxiety disorders, bipolar disorders, mania,dementia, substance-related disorders, sexual dysfunctions, eatingdisorders, obesity, anorexia or fibromyalgia is characterised in that1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineor one of its pharmaceutically acceptable salts are converted into asuitable dosage form together with at least one solid, liquid orsemiliquid excipient or adjunct

Suitable excipients are organic or inorganic substances which aresuitable for enteral (e.g. oral), parenteral or topical adminstrationand which do not react with1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineand/or one of its biocompatible salts, for example water, vegetableoils, benzyl alcohols, alkylene glycols, polyethylene glycols, glyceroltriacetate, gelatine, carbohydrates such as lactose or starch, magnesiumstearate, talc, petroleum jelly. Forms which are used for oraladministration are, in particular, tablets, pills, sugar-coated tablets,capsules, powders, granules, syrups, liquids or drops, forms for rectaladministration are, in particular suppositories, forms for parenteraladministration are, in particular, solvents, preferably oily or aqueoussolutions, furthermore suspensions, emulsions or implants, and forms fortopical administration are transdermal plasters, ointments, creams orpowders.1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineand/or one of its pharmaceutically acceptable salts may also belyophilized and the resulting lyophilisates used for example for thepreparation of injectable products. The abovementioned preparations canbe in sterilized form and/or comprise auxiliaries such as glidants,preservatives, stabilizers and/or wetting agents, emulsifiers, salts formodifying the osmotic pressure, buffer substances, colourings,flavourings and/or other active ingredients, e.g. one or more vitamins.

Preparations may, if desired, be designed to give slow release of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineor a biocompatible salt thereof.

The examples which follow relate to pharmaceutical products:

EXAMPLE A Vials

A solution of 100 g of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineor a physiologically acceptable salt thereof and 5 g of disodiumhydrogen phosphate in 3 l of twice-distilled water is brought to pH 6.5with 2N hydrochloric acid, filter-sterilized, filled into vials,lyophilized under sterile conditions and sealed in sterile form. Eachvial comprises 5 mg of active ingredient.

EXAMPLE B Suppositories

A mixture of 20 g of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineor a physiologically acceptable salt thereof is melted with 100 g ofsoya lecithin and 1400 g of cocoa butter, and the mixture is poured intomoulds and left to cool. Each suppository comprises 20 mg of activeingredient.

EXAMPLE C Solution

A solution is prepared from 1 g of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineor a physiologically acceptable salt thereof, 9.38 g of NaH₂PO₄.2H₂O,28.48 g of Na₂HPO₄.12H₂O and 0.1 g of benzalkonium chloride in 940 ml oftwice-distilled water. The pH is brought to 6.8, and the solution ismade up to 1 l and sterilized by irradiation. This solution can be usedin the form of eyedrops.

EXAMPLE D Ointment

500 mg of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineor a physiologically acceptable salt thereof are mixed with 99.5 g ofpetroleum jelly under aseptic conditions.

EXAMPLE E Tablets

A mixture of 1 kg of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineor a physiologically acceptable salt thereof, 4 kg of lactose, 1.2 kg ofpotato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate istableted in the customary manner in such a way that each tabletcomprises 10 mg of active ingredient.

EXAMPLE F Sugar-Coated Tablets

A mixture is tableted analogously to Example E, and the tablets aresubsequently coated in the customary manner with a coating of sucrose,potato starch, talc, tragacanth and colouring.

EXAMPLE G Capsules

2 kg of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineor a physiologically acceptable salt thereof are filled into hardgelatin capsules in the customary manner so that each capsule comprises20 mg of the active ingredient.

EXAMPLE H Ampoules

A solution of 1 kg of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineor a physiologically acceptable salt thereof in 60 l of twice-distilledwater is filter-sterilized, filled into ampoules, lyophilized understerile conditions and sealed in sterile form. Each ampoule comprises 10mg of active ingredient.

EXAMPLE I Spray for Inhalation

14 g of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineor a physiologically acceptable salt thereof are dissolved in 10 l ofisotonic NaCl solution, and the solution is filled into commerciallyavailable pump-operated spray containers. The solution can be sprayedinto mouth or nose. One actuation (approximately 0.1 ml) corresponds toa dose of approximately 0.14 mg.

1. A method for treating a bipolar disorder, mania or both in a patientin need thereof comprising administering to said patient an effectiveamount of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineor a physiologically acceptable salt thereof.
 2. A method according toclaim 1, wherein said patient is suffering from mania.
 3. A methodaccording to claim 1, wherein said patient is administered thepharmacologically acceptable salt is1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride.
 4. A method according to claim 1, wherein said patient isadministered the pharmacologically acceptable salt is1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride.
 5. A method according to claim 2, wherein said patient isadministered the pharmacologically acceptable salt is1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride.
 6. A method according to claim 1, wherein said patient issuffering from a bipolar disorder.
 7. A method according to claim 1,wherein1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineor a physiologically acceptable salt thereof is administered to saidpatient in a daily amount of 0.01-10 mg/kg of body weight.
 8. A methodaccording to claim 7, wherein1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride is administered to said patient in a daily amount of0.01-10 mg/kg of body weight.
 9. A method according to claim 1, wherein1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineor a physiologically acceptable salt thereof is administered to saidpatient in a dose of 0.1-500 mg.
 10. A method according to claim 9,wherein1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride is administered to said patient in a dose of 0.1-500 mg.11. A method according to claim 1, wherein1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineor a physiologically acceptable salt thereof is administered orally tosaid patient.
 12. A method according to claim 11, wherein1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride is administered orally to said patient.
 13. A methodaccording to claim 1, wherein1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineor a physiologically acceptable salt thereof is administeredintraveneously to said patient.
 14. A method according to claim 1,wherein1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride is administered intraveneously to said patient.
 15. Amethod according to claim 1, wherein1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineor a physiologically acceptable salt thereof is administeredtransdermally to said patient.
 16. A method according to claim 1,wherein1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride is administered transdermally to said patient.